tbuckley/cabot-search huggingface dataset:
The landscape of ATM alteration in Chinese solid tumor patients.
Authors: Yan Li, Qingcong Li, Yaxuan Zhang, Yuqing Lai, Zhouchao Yang, Yueqin Li, Yuehan Liao, Lu Yin, Huiting Wu, Zhengqiong Zhang, Libo Hu, Ling Li
Journal: Journal of Clinical Oncology (2023)

e15147 Background: The Ataxia-telangiectasia mutated (ATM) gene is an oncosuppressor, which plays an important role in the repair of DNA double-strand breaks (DSBs). The mutation profiles of ATM gene in Chinese solid tumor patients can help understand pathogenesis, prognosis, and identify targets for therapy. Methods: Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in normal-paired samples from 1351 patients with malignancies from January 2021 to October 2022, and alterations including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements. Results: ATM gene was altered in 6.8% (92 of 1351) of all solid tumors. The frequency of ATM variations was assessed in multiple cancer types, including non-small cell lung cancer 22% (35/159), endometrial carcinoma 15% (2/13), biliary tract tumor 12.1% (7/58), gastric cancer 10.7% (3/28), prostatic cancer 8.3% (1/12), breast cancer 6.7% (2/30), colorectal cancer 6.5% (11/168), thyroid cancer 6.2% (5/80), cervical carcinoma 5.7% (2/35), prostatic cancer 3.9% (2/51), liver cancer 3% (2/66). A total 102 genetic alterations were identified in 92 patients, including 70 missense mutations (69%), 14 nonsense (14%), 9 splicing (9%), 3 frameshift (3%), 2 deletion (2%), 2 copy number variation (2%). Among these patients, 2 had pathogenic germline ATM heterozygous mutations, including one lung adenocarcinoma and one pancreatic cancer. Furthermore, in our cohort, ATM mutation carriers also owned other actionable mutation, the most frequent one was TP53 (41%), followed by APC (29%), KRAS (23%), MLL3 (22%) and BRCA2 (20%). Conclusions: Our findings indicate that ATM alterations are widely mutated in Chinese multiple cancer types, with specific mutations differing largely among different tumor types. ATM alterations warrant further investigation as predictive biomarkers of response to PARP inhibitors or platinum-based therapy.
Real-world outcomes among patients with advanced/metastatic renal cell carcinoma (mRCC) treated with cabozantinib or other tyrosine kinase inhibitors (TKIs) after checkpoint inhibitor (CPI) therapy.
Authors: Daniel Yick Chin Heng, Gury K. Doshi, Pascale Dutailly, Aude Houchard, Mickael Lothgren, Alisha Monnette, Yunfei Wang, Valérie Perrot, Aly-Khan A. Lalani
Journal: Journal of Clinical Oncology (2023)

4530 Background: CPI-based therapy is the first-line standard of care for patients with mRCC, but effectiveness data for subsequent targeted therapies are limited. Cabozantinib, a multi-targeted TKI, is indicated for patients with mRCC in the USA and may be prescribed after doublet CPI therapy. Methods: Retrospective study of cabozantinib vs other TKI treatment after CPI therapy for mRCC using the US Oncology Network electronic health record database and chart review. Patients initiated TKI therapy between May 1, 2016 and Nov 30, 2021, immediately after CPI therapy. The primary endpoint was real-world response rate over the first 6 months of treatment (rwRR 6months ) based on physician assessment (complete response (CR): documented CR/indication of remission/disappearance of all lesions/no evidence of disease, or partial response (PR): documented PR/improved disease/responding disease). Covariates were adjusted by inverse probability of treatment weighting. Noninferiority was assessed using a 90% confidence interval (CI) and 10% noninferiority margin; if noninferiority was met, superiority was evaluated using a 95% CI and chi-square test. Results: In total, 485 patients were included. Baseline characteristics were similar for the cabozantinib and other TKIs subgroups, including proportions of patients with ≥ 2 metastatic sites (74.7% vs 68.2%) and metastases in bone (45.0% vs 43.5%), brain (8.8% vs 7.1%), liver (18.1% vs 19.5%), lung (35.0% vs 44.2%) and lymph nodes (38.7% vs 31.8%). At 6 months, tumor assessment data were available for 75.5% of patients (cabozantinib, 79.8% of cabozantinib and 66.2% of other TKIs, 66.2%) patients. Adjusted rwRR 6months was 62.5% for cabozantinib and 46.0% for other TKIs (rate difference: noninferiority, 16.5% [90% CI, 9.3–23.7], p &lt; 0.0001; superiority, 16.5% [95% CI, 7.8–25.1], p = 0.0002). Conclusions: In patients with mRCC receiving standard of care treatment in the USA, cabozantinib was effective post-CPI therapy, including in patients without prior TKI therapy. Difference in adjusted rwRR 6months significantly favored cabozantinib vs other TKIs. These data may inform global jurisdictions that restrict cabozantinib to the post TKI setting. [Table: see text]
Aggregated analysis of 1,000 patients with cancer to assess the benefits of integrated whole exome and whole transcriptome sequencing.
Authors: Konstantin Chernyshov, Anna Love, Viacheslav Senichkin, Georgy Sagaradze, Konstantin Rumyantsev, Vladimir Kushnarev, Ekaterina Postovalova, Nikita Kotlov, Anna Ogloblina, Alexander Bagaev, Nathan Fowler
Journal: Journal of Clinical Oncology (2023)

3076 Background: As the field of precision medicine rapidly expands, clinical oncologists are turning to integrated whole transcriptome (WTS) and whole exome (WES) sequencing to identify the most effective treatment options. We performed a retrospective cohort analysis of WES and WTS data from 1,000 patients with 15 major cancer types to define meaningful relationships between transcriptomic-based tumor microenvironment (TME) subtypes and pan-cancer genomic biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI) status, that are prognostic for outcome and predictive for checkpoint inhibitor response. Methods: We retrospectively analyzed WES/WTS data from cancer patients for biomarkers using our internal bioinformatics workflow. Using transcriptome-based methods described by Bagaev et al., samples were classified into one of four TME subtypes prognostic of patient outcome ( Cancer Cell, 2021). Statistical analysis consisted of Spearman’s rank correlation. Results: Comprehensive WES and WTS analysis provided by the BostonGene Tumor Portrait Test identified biomarkers based on accepted guidelines specific to the patient's cancer type in 22.5% of cases. In addition, we revealed a correlation between WTS and IHC for cancer-relevant genes, including CDX2 (R = 0.68), KRT7 (R = 0.85), KRT20 (R = 0.86), NECTIN4 (R = 0.81), and TACSTD2 (R = 0.81), indicating WTS may also be beneficial for estimating protein expression levels for cancer-specific biomarkers. Analysis of the TME showed that Fibrotic (F) and Immune Desert (D) were the most common subtypes. The F and D subtypes were linked to poor prognosis and were especially prevalent in liver and pancreatic cancers, respectively. TMB-high and MSI status were more prevalent in the immune-enriched subtypes, Immune-Enriched, Fibrotic (IE/F) and Immune-Enriched, Non-fibrotic (IE), over the less favorable F and D subtypes. The frequency of TMB-high and MSI status also differed in both IE subtypes associated with favorable prognosis, suggesting that TME subtyping provides additional prognostic power independent of TMB-high and MSI status. Conclusions: A deep interrogation of our integrated approach to genomic and transcriptomic profiling confirmed the advantages of a unified molecular analysis of tumor traits. We identified clinically significant biomarkers based on molecular features, demonstrated additional capabilities of TME analysis, and illustrated significant correlations between WTS and IHC data. These findings indicate that comprehensive WTS and WES analysis can assist clinicians in optimizing treatment plans as the landscape of personalized therapy continues to grow. [Table: see text]
Circulating tumor DNA (ctDNA) and disease recurrence in early stage pancreatic cancer.
Authors: Zimu Gong, Abdullah Esmail, Maen Abdelrahim
Journal: Journal of Clinical Oncology (2023)

e16313 Background: Surgical resection with neoadjuvant and/or adjuvant chemotherapy remains to be the cornerstone in treatment for early-stage pancreatic adenocarcinoma. Disease recurrence after curative intent treatment remains to be very common, and early detection of disease recurrence remains challenging. Recent studies explored the role of ctDNA in guiding adjuvant treatment in colon cancer, but its role in pancreatic cancer remains unknown. Methods: Through comprehensive chart review, we identified patients who: 1. Diagnosed with early-stage pancreatic adenocarcinoma; 2. Underwent curative intent surgery at our institution from 2019 to 2021; 3. Have postoperative tissue informed ctDNA results with commercially available assay (Signatera, by Natera Inc). Results: A total of 14 patients, including 7 males and 7 females, were included in the study. Depending on location of tumor, types of surgery included Whipple procedure (N = 13) and distal pancreatectomy (N = 1). The median age at time of surgery was 62 years (Range: 41-83 years). Two patients received neoadjuvant chemotherapy, and 13 patients received adjuvant chemotherapy. Two patients also received adjuvant radiation. A total of 41 ctDNA readings were obtained. The median time from surgery to first ctDNA assay was 2.4 months. First post-op ctDNA was positive in 6 patients, all of whom received adjuvant chemotherapy but still experienced clinical recurrence after a median of 3.7 months. The median overall survival of those ctDNA+ patients was 11.4 months. In the remaining 8 patients, the median progression free survival was 14 months, with clinical recurrence being observed in 4 patients. Median overall survival was not reached at median follow up of 30.5 months (one patient died at 6 months without disease recurrence, and another died at 14 months with progressive disease). In the 4 patients who had clinical recurrence despite initially negative ctDNA, ctDNA turned positive 1 month before clinical recurrence in 1 patient. However, in the other 3 patients, recurrence occurred 3.1, 1.9 and 3.5 months after the most recent negative ctDNA result. Conclusions: Our study demonstrated that positive ctDNA reliably predicts clinical recurrence in early-stage pancreatic cancer after surgery, with a positive predictive value of 100%. Negative result appears to be less reliable. This may be explained by different shedding pattern and test sensitivity. Larger scale study is underway to further evaluate its role in determining prognosis and guiding adjuvant treatment.
Genetic ancestry associations with somatic mutations in a real-world cohort of over 3,000 patients with prostate cancer.
Authors: Francisco M De La Vega, Brooke Rhead, Yannick Pouliot, Justin Guinney, David W Craig, John D. Carpten
Journal: Journal of Clinical Oncology (2023)

5034 Background: Disparities in incidence and outcomes of prostate cancer among racial groups have been reported. Black men have a higher incidence of prostate cancer compared to White men and are more likely to be diagnosed at a later stage, resulting in poorer outcomes. These differences are likely due to a combination of genetic, socioeconomic, and healthcare access factors. Furthermore, evidence has revealed racial differences in molecular profiles of prostate cancer, such as a higher incidence of ERF mutations and increased transcriptional activation of the androgen receptor signaling and inflammatory pathways in tumors derived from Black men compared to White men, suggesting that underlying biology may contribute to these disparities. Here, we aimed to identify differences in the mutational profiles of prostate cancers by race and genetic ancestry in a de-identified real-world cohort of 3,804 patients that underwent the Tempus xT 648-gene NGS tumor profiling test. Methods: We used 654 ancestry-informative markers to estimate continental ancestry likelihoods for five regions: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). We imputed Asian (ASN, n=122), Hispanic/Latino/Native American (HLN, n=300), Non-Hispanic Black (NHB, n=619) and Non-Hispanic White (NHW, n=2,679) categories using genetic ancestry thresholds based on literature and validated with available metadata. Associations between either race/ethnicity categories or continental ancestry proportions and somatic variants (copy number alterations (CNAs), small nonsynonymous, OncoKB L1/2 &amp; R1, and predicted driver somatic mutations) were assessed for 109 prostate cancer-related genes using logistic regression models. Likelihood ratio tests were used to compare models with and without race/ethnicity or ancestry terms, and the Benjamini-Hochberg method was used to adjust p-values and control the FDR at 5%. Results: NHB and ASN men had lower odds of having a PTEN CNA compared to NHW men (OR=0.58 and 0.40, p=0.0001 and 0.009, respectively). Confirming this finding was a positive association between EUR ancestry and PTEN CNAs (OR=1.07 per doubling of EUR ancestry proportion, p=0.0007). NHB men were also less likely to have actionable OncoKB somatic mutations in the PIK3CA gene when compared to NHW men (OR=0.48, p=0.03). Increased AFR ancestry was associated with the presence of nonsynonymous predicted driver mutations in SPOP (OR=1.04, p=0.04), while both EAS and SAS ancestries were associated with fewer such mutations in TP53 (OR=0.95 in both cases, p=0.02 and 0.003). Conclusions: Analysis of a large real-world cohort leveraging genetic ancestry inferred from NGS data confirms previously known associations between the presence of somatic alterations in prostate cancer genes and race/ethnicity, and identifies novel associations of potential precision therapeutic relevance.
Survival outcomes of liposomal irinotecan in patients with advanced pancreatic adenocarcinoma previously treated with conventional irinotecan-based chemotherapy: A single-institution experience.
Authors: Amol Gupta, Ihab R. Kamel, Dan Laheru
Journal: Journal of Clinical Oncology (2023)

e16260 Background: Gemcitabine-based and FOLFIRINOX (Oxaliplatin, irinotecan [IRI], 5-fluorouracil [5-FU], and leucovorin [LV]) regimens are common front-line therapies for patients with advanced pancreatic cancer (APC). Later-line options for these patients remain limited. Liposomal irinotecan (nal-IRI) plus 5-FU-LV has demonstrated a survival benefit in APC patients previously treated with gemcitabine-based treatment. However, the efficacy of nal-IRI plus 5-FU-LV in patients previously treated with conventional IRI containing regimens is controversial. Methods: A retrospective chart review was conducted on consecutive APC patients treated at our institution between November 2016 to January 2023 who completed at least one cycle of nal-IRI plus 5-FU-LV and were previously treated with conventional IRI. Data regarding survival outcomes were retrieved. The association between the survival outcomes and the interval between conventional IRI and nal-IRI was analyzed. Results: Forty-one patients met the inclusion criteria. One patient (2.4%) had a partial response (PR), and 12 patients (29.3%) had stable disease (SD) as their best response. The median overall duration of nal-IRI treatment was 2.2 (IQR: 1.4 – 5.2) months. The median progression-free survival (mPFS) was 1.9 (95% confidence interval [CI] 1.7 – 2.0) months, while the 6-month PFS rate was 24.4%. The median overall survival (mOS) was 5.9 (95% CI 3.5 – 8.2) months, and the 6-month OS rate was 48.7%. The median interval between the discontinuation of conventional IRI and starting nal-IRI was 6.5 (3.4 – 13.2) months. An interval between conventional IRI and nal-IRI ≥6.5 months was significantly associated with prolonged OS (8.5 [95% CI 5.9 - 11.1] versus 4.3 [95% CI 2.7 – 5.9] months; p = 0.017), but comparable PFS (2.0 [95% CI 1.0 – 2.8] versus 1.7 [95% CI 1.5 – 1.9] months; p = 0.052). Conclusions: Patients previously treated with conventional IRI containing regimens appear to still benefit from nal-IRI plus 5-FU-LV. A longer interval between conventional IRI and nal-IRI was associated with better OS. A sequence strategy introducing a nal-IRI-based regimen at later lines may be feasible in selected APC patients previously treated with conventional IRI, given the limited therapeutic options. Further prospective studies are warranted. [Table: see text]
Racial and income characteristics and the burden of illness among metastatic prostate cancer patients.
Authors: Satheesh kumar Poolakkad Sankaran, Joel Brian Epstein, Eric Adjei Boakye, Naheed Alam, Roberto Pili
Journal: Journal of Clinical Oncology (2023)

e17064 Background: The incidence of metastatic prostate cancer has increased dramatically between 2010 and 2017 in the United States. Since the racial and ethnic mix of the population of the United States (U.S.) have changed between the years 2010 and 2020–it is extremely important to understand its effects on prostate cancer outcomes. Therefore, we investigated the burden of illness across racial groups and income levels among patients diagnosed with metastatic prostate cancer. Methods: This study utilized the U.S. 2017 National Inpatient Sample database to identify hospitalizations with a primary diagnosis of prostate cancers. We evaluated associations between race and income levels, and the burden of illness (total charges and length of stay (LOS)) adjusting for patient and clinical factors with multivariable generalized linear models. Results: A total of 63,880 metastatic prostate cancer patients were included in the study, and the median [IQR] age was 74 [66, 82]. There were 65.6% Whites, 20.6% Blacks, 7.7% Hispanics, and 6.1% Asians and Others. Blacks had a higher prevalence in the age group 45-55 (34.2%), when compared to 55-64 (29.8%), or &gt; 65 (17.6%) age group. There were only 10% Blacks and 4.9% Hispanics living in high-income neighborhoods, whereas this was 75.5% for Whites. In the adjusted analysis, compared to the Whites, Hispanics (1.43; 95%CI-1.29- 1.57), and Asians and Others (1.39; 95%CI- 1.25- 1.56) had a higher total charge; and compared to Whites, Blacks had a higher LOS (1.28; 95%CI-1.15-1.44). Compared to high-income neighborhoods, those living in the 26th to 50th percentile had a lower total charge (0.86; 95%CI- 0.78-0.94). Compared to the &gt; 65 years age group, the 44-55 age group had a lower total charge (0.73; 95%CI-0.61-0.89). Compared to patients with Medicare, those with Private Insurance (0.87; 95%CI- 0.80-0.94) and Self-pay and Others (0.73; 95C%CI-0.62–0.86) had a lower total charge. And when compared to non-elective admissions, elective admissions had a higher total charge (1.44; 95%CI-1.29- 1.59). Conclusions: Hispanics and Asians and Others had a higher burden of illness, and Blacks had a higher LOS. Patients who reside in lower income neighborhoods had lower total charges. Understanding prostate cancer outcomes by race and income is crucial to designing strategies to improve access to care.
FLAG-IDA or venetoclax in previously treated <i>TP53</i><sup>mut</sup> acute myeloid leukemia.
Authors: Valerie Tran, Ian Michael Bouligny, Graeme Murray, Tilak Patel, Michael Doyel, Josh Boron, Juhi Gor, Yiwei Hang, Thuy Ho, Kyle Zacholski, Chad Michael Venn, Yanal Mufeed Alnimer, Nolan Wages, Steven Grant, Keri Renee Maher
Journal: Journal of Clinical Oncology (2023)

e19047 Background: Patients with del17p or TP53 mut acute myeloid leukemia (AML) have short durations of remission and dismal overall survival. The benefit of fludarabine-based intensive chemotherapy (IC), such as FLAG-IDA or FLAG, remains unclear. Additionally, while venetoclax has revolutionized the treatment of AML, the comparative efficacy of venetoclax with a hypomethylating agent (HMA; decitabine or azacitidine) remains unknown in patients with del17p or TP53 mut AML. We aimed to compare FLAG-based regimens to venetoclax + HMA in this subgroup of disease while controlling for IC candidacy. Methods: We retrospectively analyzed 79 patients with AML and TP53 mut or del17p. Of these, 25 met study inclusion criteria: age 70 or younger, treated with front-line IC, and treated with either fludarabine-based therapy (with or without idarubicin, N = 15) or venetoclax + HMA (N = 10) in the subsequent line. To further reduce confounding effects, no patients in the FLAG group received venetoclax + HMA, and no patients in the venetoclax group received FLAG. We recorded baseline patient and disease characteristics, cytogenetic risk, response, and survival. We used Fisher’s exact test for nominal data and Mann-Whitney for ordinal data. We analyzed survival by the Kaplan-Meier method and compared groups with the Mantel-Cox test. Results: We analyzed 25 patients with TP53 mut or del17p AML initially treated with IC and subsequently underwent salvage therapy with FLAG or venetoclax + HMA. The salvage regimen in each cohort was initiated after a median of one line of therapy, with no difference between groups ( p = 0.089). Patients in the FLAG cohort were significantly younger than the venetoclax cohort (54 y. vs 62 y., p = 0.046), but there were no significant differences in the Charlson Comorbidity Index scores (4 vs 4, p = 0.127) or ECOG scores (1 vs 2, p = 0.053) at salvage. There were also no differences in the median TP53 variant allele frequency (VAF) between the cohorts ( p = 0.095). The composite complete remission (CRR: CR + CRi) rate was 28.6% in the venetoclax cohort, compared to 46.7% in the FLAG cohort ( p = 0.648). Patients that received FLAG had significantly prolonged median overall survival compared to venetoclax + HMA (13.1 m. vs 4.5 m., p = 0.004). Conclusions: In patients with del17p or TP53 mut AML, FLAG-based salvage appears to offer a significant improvement in overall survival following IC failure. Prospective trial designs are needed to confirm these findings. [Table: see text]